A number of human melanoma cell lines with varying metastatic potential were used and demonstrated a positive correlation between the expression of filamin A and EGF receptor with metastasis. Pharmacological inhibition of the EGF receptor kinase and RNA interference-mediated silencing of filamin A gene were used to show marked reduction in EGF-mediated melanoma cell migration as measured by wound-healing assays. Additional experiments were carried out and established that filamin A was required for efficient EGF receptor activation, association with adaptor molecules and sorting of endocytosed receptors into the degradation pathway. The existence of a link between filamin A and the early events associated with EGF receptor activation and function could have potential therapeutic applications in cancer. Earlier studies have shown that filamin A can also interact with ROR2, an orphan tyrosine kinase receptor, whose binding with Wnt5A results in melanoma cell motility. A study using siRNA knockdown of WNT5A gene was conducted and demonstrated that filamin A expression was significantly reduced with concomitant decrease in melanoma cell motility. Additional experiments were performed and showed that the ability of Wnt5A to promote migration was ascribed to an increase in calpain 1-mediated cleavage of filamin A. Chelation of intracellular calcium and pharmacological or siRNA-mediated inhibition of calpain 1 were found to block filamin A cleavage and cell motility. These data indicate that targeting calpain-mediated cleavage of filamin A could have significant implications for tumor cell motility and invasiveness. Actin cytoskeleton remodeling that results from cleavage of filamin A may be an important integrator for the many signaling cascades that are involved in nucleocytoplasmic shuttling of nuclear receptors and regulation of their transcriptional activities.